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Ep 1472225 B1 (19) TZZ_ _T (11) EP 1 472 225 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: C07D 213/74 (2006.01) C07D 417/12 (2006.01) 28.04.2010 Bulletin 2010/17 C07D 405/12 (2006.01) A61P 23/00 (2006.01) A61K 31/44 (2006.01) (21) Application number: 03708924.0 (86) International application number: (22) Date of filing: 31.01.2003 PCT/US2003/002983 (87) International publication number: WO 2003/066595 (14.08.2003 Gazette 2003/33) (54) 2-PIPERAZINE-PYRIDINES USEFUL FOR TREATING PAIN 2-PIPERAZINPYRIDINE FÜR DIE SCHMERZBEHANDLUNG 2-PIPERAZINE-PYRIDINES UTILES POUR LE TRAITEMENT DE LA DOULEUR (84) Designated Contracting States: (72) Inventors: AT BE BG CH CY CZ DE DK EE ES FI FR GB GR • KYLE, Donald, J. HU IE IT LI LU MC NL PT SE SI SK TR Newtown, PA 18940 (US) • SUN, Qun (30) Priority: 01.02.2002 US 352855 P Princeton, NJ 08540 (US) 17.09.2002 US 411043 P (74) Representative: Maiwald, Walter (43) Date of publication of application: Maiwald Patentanwalts GmbH 03.11.2004 Bulletin 2004/45 Elisenhof Elisenstrasse 3 (60) Divisional application: 80335 München (DE) 08017729.8 / 2 033 951 (56) References cited: (73) Proprietor: EURO-CELTIQUE S.A. WO-A-02/08221 WO-A-02/08221 1653 Luxembourg (LU) Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations. Notice of opposition shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 1 472 225 B1 Printed by Jouve, 75001 PARIS (FR) EP 1 472 225 B1 Description [0001] The present invention relates to Piperazine Compounds; compositions comprising a Piperazine Compound; and methods for preventing or treating pain, urinary incontinence (UI), an ulcer, inflammatory-bowel disease (IBD), 5 irritable-bowel syndrome (IBS), an addictive disorder, Parkinson’s disease, parkinsonism, anxiety, epilepsy, stroke, a seizure, a pruritic condition, psychosis, a cognitive disorder, a memory deficit, restricted brain function, Huntington’s chorea, amyotrophic lateral sclerosis (ALS), dementia, retinopathy, a muscle spasm, a migraine, vomiting, dyskinesia or depression, comprising administering to an animal in need thereof an effective amount of a Piperazine Compound. 10 2. BACKGROUND OF THE INVENTION [0002] Pain is the most common symptom for which patients seek medical advice and treatment. Pain can be acute or chronic. While acute pain is usually self-limited, chronic pain persists for 3 months or longer and can lead to significant changes in a patient’s personality, lifestyle, functional ability and overall quality of life (K.M. Foley, Pain, in Cecil Textbook 15 of Medicine 100-107 (J.C. Bennett and F. Plum eds., 20th ed. 1996)). [0003] Pain has been traditionally managed by administering non-opioid analgesics, such as acetylsalicylic acid, choline magnesium trisalicylate, acetaminophen, ibuprofen, fenoprofen, diflusinal, and naproxen; or opioid analgesics, including morphine, hydromorphone, methadone, levorphanol, fentanyl, oxycodone, and oxymorphone. Id. [0004] UI is uncontrollable urination, generally caused by bladder-detrusor-muscle instability. UI affects people of all 20 ages and levels of physical health, both in health care settings and in the community at large. At present, UI afflicts 15-30% of elderly people living at home, one-third of those living in acute-care settings, and at least one-half of those living in long-term care institutions (R.M. Resnick, Lancet 346:94 (1995)). Persons having UI are predisposed to also having urinary-tract infections, pressure ulcers, perineal rashes and urosepsis. Psychosocially, UI is associated with embarrassment, social stigmatization, depression and a risk of institutionalization (Herzo et al., Annu. Rev. Gerontol. 25 Geriatr. 9:74 (1989)). Economically, the costs of UI are great; in the United States alone, health-care costs associated with UI are over $15 billion per annum. [0005] Physiologic bladder contraction results in large part from acetylcholine-induced stimulation of post-ganglionic muscarinic-receptor sites on bladder smooth muscle. Treatments for UI include the administration of drugs having bladder-relaxant properties, which help to control bladder-detrusor-muscle overactivity. For example, anticholinergics 30 such as propantheline bromide and glycopyrrolate, and combinations of smooth-muscle relaxants such as a combination of racemic oxybutynin and dicyclomine or an anticholinergic, have been used to treat UI (See, e.g., A.J. Wein, Urol. Clin. N. Am. 22:557-577 (1995); Levin et al., J. Urol. 128:396-398 (1982); Cooke et al., S. Afr. Med. J. 63:3 (1983); R.K. Mirakhur et al., Anaesthesia 38:1195-1204 (1983)). These drugs are not effective, however, in all patients having unin- hibited bladder contractions. Administration of anticholinergic medications represent the mainstay of this type of treat- 35 ment. [0006] None of the existing commercial drug treatments for UI, however, has achieved complete success in all classes of UI patients, nor has treatment occurred without significant adverse side effects. For example, drowsiness, dry mouth, constipation, blurred vision, headaches, tachycardia, and cardiac arrhythmia, which are related to the anticholinergic activity of traditional anti-UI drugs, can occur frequently and adversely affect patient compliance. Yet despite the prev- 40 alence of unwanted anticholinergic effects in many patients, anticholinergic drugs are currently prescribed for patients having UI. The Merck Manual of Medical Information 631-634 (R. Berkow ed., 1997). [0007] Ulcers are sores occurring where the lining of the digestive tract has been eroded by stomach acids or digestive juices. The sores are typically well-defined round or oval lesions primarily occurring in the stomach and duodenum. About 1 in 10 people develop an ulcer. Ulcers develop as a result of an imbalance between acid-secretory factors, also 45 known as "aggressive factors," such as stomach acid, pepsin, and Helicobacter pylori infection, and local mucosal- protective factors, such as secretion of bicarbonate, mucus, and prostaglandins. [0008] Treatment of ulcers typically involves reducing or inhibiting the aggressive factors. For example, antacids such as aluminum hydroxide, magnesium hydroxide, sodium bicarbonate, and calcium bicarbonate can be used to neutralize stomach acids. Antacids, however, can cause alkalosis, leading to nausea, headache, and weakness. Antacids can 50 also interfere with the absorption of other drugs into the blood stream and cause diarrhea. [0009] H2 antagonists, such as cimetidine, ranitidine, famotidine, and nizatidine, are also used to treat ulcers. H2 antagonists promote ulcer healing by reducing gastric acid and digestive-enzyme secretion elicited by histamine and other H2 agonists in the stomach and duodenum. H2 antagonists, however, can cause breast enlargement and impotence in men, mental changes (especially in the elderly), headache, dizziness, nausea, myalgia, diarrhea, rash, and fever. 55 [0010] H+,K+ - ATPase inhibitors such as omeprazole and lansoprazole are also used to treat ulcers. H+,K+ - ATPase inhibitors inhibit the production of enzymes used by the stomach to secrete acid. Side effects associated with H+,K+ - ATPase inhibitors include nausea, diarrhea, abdominal colic, headache, dizziness, somnolence, skin rashes, and tran- sient elevations of plasma activities of aminotransferases. 2 EP 1 472 225 B1 [0011] Sucraflate is also used to treat ulcers. Sucraflate adheres to epithelial cells and is believed to form a protective coating at the base of an ulcer to promote healing. Sucraflate, however, can cause constipation, dry mouth, and interfere with the absorption of other drugs. [0012] Antibiotics are used when Helicobacter pylori is the underlying cause of the ulcer. Often antibiotic therapy is 5 coupled with the administration of bismuth compounds such as bismuth subsalicylate and colloidal bismuth citrate. The - bismuth compounds are believed to enhance secretion of mucous and HCO3 , inhibit pepsin activity, and act as an antibacterial against H. pylori. Ingestion of bismuth compounds, however, can lead to elevated plasma concentrations of Bi+3 and can interfere with the absorption of other drugs. [0013] Prostaglandin analogues, such as misoprostal, inhibit secretion of acid and stimulate the secretion of mucous 10 and bicarbonate and are also used to treat ulcers, especially ulcers in patients who require nonsteroidal anti-inflammatory drugs. Effective oral doses of prostaglandin analogues, however, can cause diarrhea and abdominal cramping. In addition, some prostaglandin analogues are abortifacients. [0014] Carbenoxolone, a mineral corticoid, can also be used to treat ulcers. Carbenoxolone appears to alter the composition and quantity of mucous, thereby enhancing the mucosal barrier. Carbenoxolone, however, can lead to Na+ 15 and fluid retention, hypertension, hypokalemia, and impaired glucose tolerance. [0015] Muscarinic cholinergic antagonists such as pirenzapine and telenzapine can also be used to reduce acid secretion and treat ulcers. Side effects of muscarinic cholinergic antagonists include dry mouth, blurred vision, and constipation. The Merck Manual of Medical Information 496-500 (R. Berkow ed., 1997) and Goodman and Gilman’s The Pharmacological Basis of Therapeutics 901-915
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